title: Early expression of the fractalkine receptor CX3CR1 in pancreatic carcinogenesis.
abstract: BACKGROUND
  In pancreatic ductal adenocarcinoma (PDAC), fractalkine receptor CX3CR1 contributes to perineural invasion (PNI). We investigated whether CX3CR1 expression occurs early in PDAC and correlates with tumour features other than PNI.
  
  
  METHODS
  We studied CX3CR1 and CX3CL1 expression by immunohistochemistry in 104 human PDAC and coexisting Pancreatic Intraepithelial Neoplasia (PanIN), and in PdxCre/LSL-Kras(G12D) mouse model of PDAC. CX3CR1 expression in vitro was studied by a spheroid model, and in vivo by syngenic mouse graft of tumour cells.
  
  
  RESULTS
  In total, 56 (53.9%) PDAC expressed CX3CR1, 70 (67.3%) CX3CL1, and 45 (43.3%) both. CX3CR1 expression was independently associated with tumour glandular differentiation (P=0.005) and PNI (P=0.01). Pancreatic Intraepithelial Neoplasias were more frequently CX3CR1+ (80.3%, P<0.001) and CX3CL1+ (86.8%, P=0.002) than matched cancers. The survival of PDAC patients was better in those with CX3CR1+ tumour (P=0.05). Mouse PanINs were also CX3CR1(+) and -CL1(+). In vitro, cytokines significantly increased CX3CL1 but not CX3CR1 expression. Differently, CX3CR1 was upregulated in tumour spheroids, and in vivo only in well-differentiated tumours.
  
  
  CONCLUSIONS
  Tumour differentiation, rather than inflammatory signalling, modulates CX3CR1 expression in PanINs and PDAC. CX3CR1 expression pattern suggests its early involvement in PDAC progression, outlining a potential target for interfering with the PanIN transition to invasive cancer.
authors.affiliation: Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Celesti
authors.forename: G
authors.initials: G
authors.lastname: Di Caro
authors.forename: P
authors.initials: P
authors.lastname: Bianchi
authors.forename: F
authors.initials: F
authors.lastname: Grizzi
authors.forename: F
authors.initials: F
authors.lastname: Marchesi
authors.forename: G
authors.initials: G
authors.lastname: Basso
authors.forename: D
authors.initials: D
authors.lastname: Rahal
authors.forename: G
authors.initials: G
authors.lastname: Delconte
authors.forename: M
authors.initials: M
authors.lastname: Catalano
authors.forename: P
authors.initials: P
authors.lastname: Cappello
authors.forename: M
authors.initials: M
authors.lastname: Roncalli
authors.forename: A
authors.initials: A
authors.lastname: Zerbi
authors.forename: M
authors.initials: M
authors.lastname: Montorsi
authors.forename: F
authors.initials: F
authors.lastname: Novelli
authors.forename: A
authors.initials: A
authors.lastname: Mantovani
authors.forename: P
authors.initials: P
authors.lastname: Allavena
authors.forename: A
authors.initials: A
authors.lastname: Malesci
authors.forename: L
authors.initials: L
authors.lastname: Laghi
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D054428:Chemokine CX3CL1 / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000235:genetics; D012189:Retrospective Studies; D015854:Up-Regulation
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine